HU180628B - Process for preparing new dibenzo-azepines,-oxazepines and thiazepines - Google Patents

Description

The present invention relates to novel heterocyclic compounds of the formula I and to pharmaceutical compositions containing them. In this formula, R ₁ , R ₂ , R ₃ and R _{4 are} hydrogen or halogen, 5 or C 1-6 alkyl or alkoxy, R ₅ and R _{e are} hydrogen, C 1-6 alkyl or C 3-6 alkenyl, R ₅ and R ₆ together with the nitrogen atom are pyrrolidino, piperidino or morpholino; and 10

X represents an oxygen or sulfur atom or a methylene group (-CH ₂ -).

The novel compounds of the invention may be prepared as racemates or pure enantiomers or mixtures thereof in which the proportion of enantiomers is variable. The compounds may be prepared as the free base or as acid addition salts.

The groups R 1 -R ₄ , R ₅ and R ₆ independently of one another may be straight or branched alkyl, alkoxy or alkenyl groups. Thus, alkyl groups may be methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl,

2-methyl-butyl, 1-methyl-butyl, neopentyl, 1,1-din-ethyl-propyl, 1,2-di-ethyl-propyl, hexyl, 4-n-ethyl-25-pentyl, 3-methylpentyl, 2-ethyl-pentyl, 1-methyl-pentyl, 1,1-dimethyl-butyl, 2,2-dimethyl-butyl, 3,3-dimethyl-butyl, 2-dimethyl-butyl, 1,3-dimethyl-butyl, 1,1,2-trimethyl-propyl, 1,2,2-trimethyl-propyl, 2-ethyl-butyl or 1-ethyl-butyl -group. 30

The carbon chain of the alkoxy groups is the same as above.

The compounds of formula I (where R ₆ and optionally R _s is hydrogen) a la tautomeric cyclic guanidine derivatives of the general form may exist.

The formula Ib illustrates the position of the substituents.

The novel compounds of formula I or Ia according to the invention may be prepared by the following processes:

a) A compound of formula II, in which Y represents a halogen atom such as chlorine, alkoxy or alkylthio, is reacted with an amine of formula III.

The reaction is carried out in a melt or in known solvents (e.g., alcohols, ketones, ethers, aliphatic or aromatic hydrocarbons), optionally in an autoclave.

Amines of formula III are also suitable as reaction media. The reaction is generally carried out at a temperature ranging from the boiling point of the solvents.

The starting compounds of formula II may be prepared in a manner known in the art; when Y is a halogen in formula II, for example, a diamine of formula IV is reacted with a bifunctional carbonic acid derivative such as phosgene, chloro-carbonic acid ester or N, N'1 carbonyl-dinidazole to give the starting compound II

The oxo compound of formula V, wherein Z is oxygen, is halogenated with an inorganic acid chloride.

Compounds of formula II wherein Y represents an alkylthio group are prepared, for example, by reacting a diamine of formula IV with carbon disulfide, thiophosphene or N, N'-thiocarbonyldiimidazole.

The 3-thioxo derivative of formula V, wherein Z is sulfur in formula 1J, is alkylated with an alkyl halide to a compound of formula II in which Y is alkylthio. When Y in formula II is an alkoxy or alkylthio group, the alkyl group is preferably 1! 1-8 carbon monofilament and may be substituted.

The diamines of formula IV can be prepared according to Scheme [A].

Compounds of formula VI are known in the art, e.g. Chitra. Aeta 49/11. 2i p. 1433 (1966) or Helv. Chini. Acta 50/1. 245 (1967)] or may be prepared in a known manner. Reaction of a compound of formula VI with an alkali cyanide such as sodium ciaridide, preferably in dimethylsulfoxide at room temperature, does not exceed 2%. 60 ° C. The cyano compounds of formula VII are preferably reduced with lithium aluminum hydride (LiAlH ₄ ) or aluminum hydride (AlH ₃ ) in tetrahydrofuran or diethyl ether.

b) A diamine of the formula TV is reacted with a halocyanide such as bromocyanide according to Scheme [B]. The resulting I and Ia is meant any pharmaceutically acceptable general formula _R5 and _R6 are hydrogen.

The reaction is preferably carried out at room temperature in a mixture of ethanol 3 and tetrahydrofuran, but may also be carried out in other solvents such as alcohol, chloroform or a hydrocarbon such as toluene, xylene, etc., optionally in the presence of a base additive (e.g. potassium carbonate). The reaction temperature can be varied in a wide range up to the boiling point of the reaction mixture.

An intermediate of the reaction of a compound of formula IV with, for example, bromene, yields a compound of formula IVa; this is actually the starting material for the ring closure reaction I. It is not necessary to isolate this compound since the reaction proceeds smoothly until the desired final product is formed.

c) A compound of formula VIII is cyclized. In this formula, R _x -R _e is as defined above and Q is oxygen or sulfur or = NR-, wherein R _{7 is} hydrogen or optionally substituted C 1-8 alkyl, such as methyl, is ethyl, propyl or benzyl.

Those compounds of formula VIII, wherein Q is oxygen or sulfur, R ₅ and R _e alkenilesöpörtot alkyl or both hydrogen (mot means, is prepared by reacting a diamine of formula IV izoeianáttal alkyl or alkenyl or alkyl or alkenyl isothiocyanate.

For the preparation of the compounds of formula I or Ia according to the invention, the ring closure is carried out by reaction with acid halides, such as phosphoryl trichloride, optionally in a known solvent such as toluene. In another embodiment, the sulfur atom of the thiourea derivative of formula VIII, wherein Q is sulfur, is alkylated to give an alkylthio of formula IX, wherein R is C 1-8 optionally substituted alkyl, followed by the reaction of formula IX. alkylthiochloride is prepared by ring closure of a compound of formula I or Ia by heating in a known manner in a solvent such as alcohols, toluene or as a melt.

Compounds of formula VIII wherein Q = NR- may be prepared, for example, by reacting a diamine of formula IV with a substituted or unsubstituted S-alkylisothiourea. Preferably, the ring closure is carried out in a melt to produce the compounds of formula I and Ia.

d) A diamine of formula IV is reacted with a Ν, Ν-disubstituted dichloromethyleniminium salt of formula X according to reaction equation [C].

Thus a formula I compound having a formula of R ₅ and R ₆ are as defined above, but other than hydrogen. The reaction is preferably carried out in an inert solvent such as chloroform in the presence of a base additive such as triethylamine.

The reaction products prepared according to the above procedures are isolated by known laboratory methods. Optionally, the resulting crude products may be purified by special techniques such as column chromatography before crystallization in the form of a base or a suitable salt.

If desired, the racemates of the present invention can be converted to the enantiomer by known methods.

Free bases can be prepared from primary salts, if desired, and acid addition salts from primary free bases, if desired.

Particularly suitable acids for the preparation of acid addition salts are those which are suitable for the formation of pharmaceutically acceptable salts.

Suitable acids include, for example, hydrogen halides, aliphatic, alicyclic aromatic or heterocyclic carboxylic acids, or sulfonic acids such as acetic, tartaric, malonic, citric, fumaric, salicylic, ambonic, urethanesulfonic, toluenesulfonic; and sulfuric acid and phosphoric acid.

The novel compounds of the present invention are useful as pharmaceuticals or as intermediates for the preparation of pharmaceutical compounds. With relatively low toxicity, they are persistently antiallergic, histamine inhibiting and antiserotonic, and inhibit the aggregation of blood cells. For example, the novel compounds of the present invention are useful in the treatment of histamine or serotonin release reactions such as bronchial asthma, allergic bronchitis, allergic rhinitis, allergic conjunctivitis and allergic hypersensitivity symptoms. In particular, when used as a medicament, the compounds are very effective in oral treatment. The oral activity of the compound of the invention provides a significant advantage over the commercially available disodium salt of known chromoglycolic acid for the treatment of bronchial asthma and allergic bronchitis.

The active ingredient of the present invention may be formulated with excipients and carriers in conventional manner into conventional galenical formulations, for example capsules, tablets, dragees, solutions and suspensions for oral use; for pulmonary administration into aerosol formulations; for parenteral use, as isotonic aqueous solutions, and for topical application as creams, ointments, lotions, emulsions or sprays. For oral administration, the daily dose for adults is 0.2-40 mg, preferably about 0.5-10 mg. For inhalation, a single dose is 0.05 to 20 mg, preferably 0.2 to 5 mg; conventional formulations, in particular aerosol formulations for administration and capsules for inhalation of the powder, are used. Single doses may be given several times daily.

Pharmacological studies were conducted to determine the efficacy of the compound of the invention.

a) Experiments were performed on allergic rats after passively sensitizing the animals with IgE antibodies and subsequent antigen challenge. thus, passive skin hypersensitivity (Goose et al. (1969): Immunology 16, 749) (PCA) and passive time hypersensitivity (Farmer et al. (1975): Br. J. Pharmac. 55, 57] (PLA, experimental asthma).

b) The oral anaphylactic activity of the compounds of the present invention was demonstrated in experiments in dogs that are hypersensitive to intestinal mildew antigen (Boots et al., 1970, J. Foot. clin. Med. 76, 181],

(e) Antihistamines and antiserotonics:

The compounds of the invention were administered orally and intravenously to rats, dogs and monkeys to inhibit histamine urticaria induced by the intravenous injection of histamine. Quantitative evaluation was performed by injecting Evans blue dye into the skin and measuring urticaria.

The antiserotonin activity of the compound of the invention was demonstrated by its activity against the serotonin edema in the paw of rats (Doepener et al. (1958) Int. Areh. Allergv, 12, 89],

As an example, the following table illustrates the invention

Compound PCA ED _S0 mg / kg rat po PLA ED ₅₀ LD ₅₀ mg / kg rat arc. mg / k £ mouse p.o. Example 1 6 0,052 325 Example 1 (a) 0.96 - - Example 1 (c) 1.1 - 340 Example 1 (d) 2.5 - - Example 1 (i) 3.8 - - Example 1 (1) 5.4 - -

Data illustrating the effects of the compounds of Formula I are summarized.

The following is an example of pharmaceutical compositions containing the active compounds of the invention:

tablets

Ingredients:

The active ingredient of the formula I is 0.005 g of stearic acid 0.001 g of glucose 0.194 g

Aerosol inhaler

Ingredients:

The active ingredient of the formula I is supplemented with 1.00 parts of soy lecithin and 0.20 parts of propellant mixture (Frigen 11, 12 and 114) to 100.00 parts.

Preferably, the composition is filled into a metered dose aerosol bottle and the single dose is adjusted to contain 0.5 mg of the active ingredient. For other dosages within the stated range, compositions containing more or less active ingredients are desirably employed.

Capsule Inhaler

A microparticulate active ingredient of formula I (having a particle size predominantly in the range of 2 to 6 µ.τη) is optionally filled into hard gelatine capsules by the addition of microparticulate carriers such as lactose. Devices used for inhalation treatment are suitable for inhalation. For example, one capsule contains 0.2 to 20 mg of active ingredient and 0 to 40 mg of lactose.

Ointment

Ingredients: g / 100 g ointment an agent of the invention 2,000 fuming hydrochloric acid 0.011 nátriumpiroszulfit 0,050 equal parts cetyl alcohol and stearyl alcohol blend 20,000 white petrolatum 5,000 artificial bergamot oil 0,075 filled with distilled water 100,000s. The ingredients are worked in the usual way ointment.

The following examples illustrate the process of the invention.

Example 1

3-Amino-9,13b-dihydro-1H-dibenz [c, f] imidazo [1,5-a] jazepine hydrobromide

6-Aminomethyl-6,11-dihydro-5 H -dibenz [b, e] azepine (6.72 g, 0.03 mol) was dissolved in ethanol (60 ml), while stirring to a solution of 3.18 g (0.03 mol) of bromocyanide. of anhydrous tetrahydrofuran solution was added dropwise. The reaction mixture was stirred at room temperature overnight and then ether (50 mL) was added and the precipitated crystalline material was filtered off with suction.

Yield: 7.8 g (78.9%); 284-286 ° C (CH2OH / ethyl acetate).

The base liberated from the hydrobromide in aqueous sodium hydroxide has a melting point of 205-208 ° C (from acetonitrile).

To prepare the hydrochloride salt, a methanolic suspension of the base is reacted with a calculated amount of ethereal hydrochloric acid and then the hydrochloride salt is separated off by adding ether.

272-273 ° C (from methanol / ether).

In analogy to Example 1, the following compounds can be prepared:

(a) 3-Amino-7-chloro-9,13b-dihydro-1H-dibenz [c, f] -imidazo [1-5] jasepine hydrochloride: m.p. 325-329 ° C (dec.).

(Alcohol);

(b) 3-amino-6-methyl-9,13b-dihydro-1H-dibenz [c. f] -imidazo- [1,5-a] azepine hydrobromide;

(c) 3-amino-1,13b-dihydro-dibenz [b, f] imidazo [1,5-d] [1,4] -oxazepine hydrobromide, m.p. 261-264 ° C (from alcohol / ethyl acetate);

(d) 3-amino-12-chloro-1,13b-dihydro [b, f] imidazo [1,5-d] [1,4] oxazepine hydrobromide, m.p. 300 ° C (from acetonitrile / ethyl acetate);

(e) 3-amino-7-chloro-1,13b-dihydrodibenz [b, f] imidazo [1,5-d] - [1,4] oxazepine hydrobromide, m.p. 297-300 ° C (from alcohol / ether). );

(f) 3-amino-6-chloro-1,13b-dihydro-dibenz [b, f] imidazo [1,5-d] - [1,4] oxazepine hydrobromide, m.p. 282-284 ° C. methanol and ether);

(g) 3-amino-6-methyl-1,3b-dihydro-dibenz [b, f] imidazo [1,5-d] - (1,4) oxazepine hydrobromide, m.p. 187-189 ° C;

(h) 3-amino-12-methyl-1,13b-dihydro-dibenz [b, f] imidazo [1,5-d] - [1,4] oxazepine hydrobromide, m.p. 309-312 ° C;

(i) 3-Amino-1,13b-dihydro-dibenz [h, f] imidazo [1,5-d] [1,4] -thiazepine, hydrobromide.

To prepare the acid maleate (C ₁₅ H ₁₃ N ₃ S x C ₄ H ₄ O ₄ ), the known liberated base is dissolved in methanol and a calculated amount of maleic acid is added. The precipitated crystals were recrystallized from methanol in the presence of activated carbon, m.p. 230 ° C.

(j) 3-amino-6-chloro-1,13b-dihydro-dibenz [b, f] imidazo [1,5-d] - [1,4] thiazepine hydrobromide;

(k) 3-amino-7-chloro-1,13b-dihydro-dibenz [b, f] imidazo [1,5-d] - ([1,4] thiazepine, hydrobromide);

(1) 3-amino-12-chloro-1,13b-dihydro-dibenz [b, f] imidazo [1,5-d] - [1,4] thiazepine, hydrobromide; m.p. 358-361 ° C (dec.), (from methanol / ethyl acetate);

(m) 3-amino-6-methyl-1,13b-dihydro-dibenz [b, f] imidazo [1,5-d] - [1,4] thiazepine hydrobromide;

(n) 3-amino-6-methoxy-1,13b-dihydro-dibenz [b, f] -imidazo [1,5-d] - [1,4] thiazepine hydrobromide;

The diamine starting material of formula IV can be prepared according to Scheme [A], for example: 11-Aminomethyl-7-chloro-10,11-dihydrodibenz [b, f] [1,4] oxazepine fumar (I). 7-Chloro-11-cyano-dibenz [b, f] [1,4] oxazepine

A suspension of 123 g (0.47 mol) of 7,11-dichlorodibenz [b, f] [1,4] oxazepine and 46 g (0.94 mol) of sodium cyanide in 1400 ml of dimethylsulfoxide was heated at 50-60 ° C for 3 hours. stirred. The reaction mixture was cooled and poured into ice water (6 L). It was then extracted with chloroform, dried over anhydrous sodium sulfate, and the organic phase was concentrated in vacuo. The crystalline product was washed with methanol and dried.

Yield: 74 g (62.4%). 185-188 ° C.

In analogy to the above, the following cyano compounds can be prepared:

(a) 8-chloro-11-cyano-dibenz [b, f] [1,4] oxazepine; yield: 69.7%; 161-163 ° C (from acetonitrile);

(b) 2-chloro-11-cyano-dibenz [b, f] [1,4] oxazepine; Yield: 31.4%; 126-132 ° C (crude product);

(e) 11-cyano-dibenz [b, f] [1,4] oxazepine; yield: 85.7%; mp 107-114 ° C;

(d) 11-cyano-dibenz [b, f] [1,4] thiazepine; yield: 100%; mp 93-100 ° C;

(e) 2-chloro-11-cyano [b, f] [1,4] thiazepine; yield: 65.3%, mp 176-182 ° C;

(f) 6-cyano-11 H -dibenz [b, e] azepine; Yield: 73.2%, m.p. 98-100 ° C (from methanol);

(g) 2-chloro-6-cyano-11 H -dibenz [b, e] azepine; Yield: 67.5%, m.p. 163-168 ° C.

(II) Reduction of 7-chloro-11-cyano-dibenz [b, f] [1,4] oxazepine prepared according to (I)

A solution of aluminum hydride in tetrahydrofuran was prepared by stirring a solution of 7.8 g (0.2 mol) of lithium aluminum hydride in 200 ml of anhydrous tetrahydrofuran in 40 ml of anhydrous tetrahydrofuran with stirring. ice. Without isolation of the lithium sulfate obtained, a solution of 7-chloro-11-cyano-dibenz [b, f] - [1.4] oxazepine (12.3 g, 0.05 mol) in 80 ml of anhydrous tetrahydrofuran was added over a period of 2 hours. stirring is continued at room temperature. After cooling with ice, the excess hydride was decomposed by addition of 25 ml of water. The inorganic compounds are filtered off with suction and treated twice with chloroform. The tetrahydrofuran solution and the chloroform solution were combined, washed with an aqueous solution of sodium chloride and dried over sodium sulfate. It is then concentrated in vacuo. 25 g of a dark red oil are obtained. It is purified by dissolution in matanol and converted to a sour fumarate salt by adding a calculated amount of fumaric acid.

Yield: 26 g (71.3%). Mp 228 ° C.

The following diamines were prepared as described in (II):

(a) 11-Aminomethyl-8-chloro-10,11-dihydro-dibenz [b, f] - [1.4] -oxazepine fumarate; yield: 54.6%, m.p. 239-241 ° C (dec.);

(b) 11-Aminomethyl-2-chloro-10,11-dihydro-dibenz [b, f] - [1,4] -oxazepine fumarate; yield: 54.4%, m.p. 228-229 ° C (dec.); 131-133 ° C (from acetonitrile);

(c) 11-aminomethyl-10,11-dihydro-dibenz [b, f] (1,4) oxazepine, 65.5%, mp 119-122 ° C (from acetonitrile);

(d) 11-aminomethyl-10,11-dihydrodibenz [b, f] [1,4] thiazepine fumarate; yield: 61%; mp 204-206 ° C (dec.);

(e) 11-Aminomethyl-2-chloro-10,11-dihydro-dibenz [b, f] [1,4] thiazepine fumarate; yield: 68.8%; mp 202 ° C (dec.);

(f) 6-aminomethyl-6,1-dihydro-5H-dibenz [b, e] aze 4 -fumarate; yield: 72.3%; m.p. 192-193 ° C (dec.);

(g) 6-aminomethyl-2-chloro-6,1-dihydro-5H-dibenz [b, e] azepine fumarate; Yield: 42.1%, m.p. 197-198 ° C (dec.).

Example 2

3-Morpholino-1,13b-dihydro-dibenz [b, f] imidazo [1,5-d] [1,4] oxazepine fumarate (I) 3-Methylthio-1,13b-dihydro-dibenz [b, f] imidazo [1,5-

d] [1,4] -oxazepine hydroiodide g (0.075 mol) 1,2,3,13b-tetrahydro-dibenz [b, f] imidazo [1,5-d] [1,4] oxazepine-3-thione, ( m.p. 199-201 ° C and prepared from 11-aminomethyl-10,11-dihydro-dibenz [b, f] [1,4] oxazepine and carbon disulfide) 21.4 g (0.15 mol) of methyl iodide in 170 ml of methanol and the reaction mixture was refluxed for 3 hours. First, a clear solution is obtained which gradually precipitates a crystalline material. After cooling, the precipitate is filtered off with suction and dried.

Yield: 26.6 g (87%); mp 219-228 ° C (dec.).

In analogy to the above, for example, 6-aminomethyl-

From 6,1 l-dihydro-5 H -dibenz [b, e] azepine 2,3,9,13b-tetrahydro-1 H-dibenz [c, f] imidazole [1,5-a] azepine-3-thione (m.p. 222 -224'C) to give 3-methylthio-9,13b-dihydro-1H-dibenz [c, f] imidazo [1,5-a] azepine hydroiodide (m.p. 274- 283 ° C).

The 3-methylthio derivatives can be further processed without purification.

(II) 8.2 g (0.02 mol) of 3-methylthio-1,13b-dihydro-dibenz [b, f] -imidazo [1,5-d] [1,4] oxazepine hydroiodide mixed with 25 ml of morpholine and heating under reflux. The light yellow solution was concentrated in vacuo and the residue partitioned between ether and 2N sodium hydroxide solution. The organic phase is then washed with water, dried over sodium sulfate and evaporated. The residue was recrystallized from acetonitrile (m.p. 141-142 ° C). To obtain the acid fumarate salt, the resulting base is dissolved in alcohol and reacted with a calculated amount of fumaric acid. After cooling, 5.8 g (66.4%)

3-Morpholino-1,13b-dihydro-dibenz [b, f] -imidazo [1,5-d] [1,4] oxazepine hydrogen fumarate is obtained. 189-191 ° C (dec.).

In a manner analogous to that described in (II), the following compounds can be prepared from the corresponding methylthio compounds:

(a) 3- (n-pentylamino) -9,13b-dihydro-1 H -dibenz [c, f] imidazo- [1,5-a] azepine; m.p. 192-195 ° C.

(b) 3-morpholino-9,13b-dihydro-ΙΗ-dibenz [c, f] imidazo [1,5-a] azepine hydrochloride; mp 204-207 ° C (dec.).

Example 3

3-Allylamino-9,13b-dihydro-dibenz [b, f] imidazo [1,5-d] [1,4] oxazepine hydrochloride

8.2 g (0.02 mol) of 3-methylthio-1,13b-dihydro-dibenz [b, f] -imidazo [1,5-d] [1,4] oxazepine-hydroiodide 3.42 g (0, 06 mol) of allylamine was heated at 70 ° C for 2 hours with stirring. After cooling, 2N sodium hydroxide solution was added to the light yellow oil and extracted with ether. The organic layer was separated, washed with water and dried over anhydrous sodium sulfate. Concentration in vacuo gave 5.6 g of crude product which was converted to the hydrochloride using methanolic hydrochloric acid in a known manner.

Yield: 4.1 g (62.6%). 189-192 ° C (from acetonitrile).

Example 4

3-Dimethylamino-1,13b-dihydro-dibenz [b, f] imidazo [1,5-d] [1,4] -oxazepine hydrochloride g (7.4 mol) 3-methylthio-1,13b-dihydro- Dibenz [b, f] imidazo [1,5-d] [1,4] oxazepine hydroiodide was heated in an autoclave at 130 ° C for 3 hours with a solution of 15 ml of dimethylamine in 30 ml of ethanol. After evaporation of the reaction mixture, the resin was mixed with chloroform and extracted with 2N sodium hydroxide solution. The organic phase was dried over sodium sulfate and the solvent was distilled off in vacuo.

2.6 g of an oil are obtained (crude base) which is converted into the hydrochloride salt (m.p. 163-167 ° C) from acetonitrile / ether with methanolic hydrochloric acid. The product contains 1 mol of water (Karl-Fischer titration).

In analogy to Example 4, the following compounds can be prepared from the corresponding methylthio derivatives:

(a) 3-dimethylamino-9,13-dihydro-1H-dibenz [c, f] imidazo [1,5-a] azepine hydrochloride; mp 268-271 ° C;

(b) 3-dimethylamino-1,13b-dihydro-dibenz [b, f] imidazo [1,5-d] [1,4] thiazepine hydrochloride; mp 241-244 ° C (containing 0.5 moles of water).

Under similar reaction conditions as above

By reaction of 3-methylthio-9,11b-dihydro-1H-dibenz [c, f] imidazo [1,5-a] azepine hydroiodide and ammonia, respectively, the following compounds were prepared:

(c) 3-Amino-9,13b-dihydro-dib-dibenz [c, f] imidazo [1,5-a] azepine hydrochloride (m.p. 283-286 ° C). Identical to the product prepared in Example 1.

(d) 3-pyrrolidino-9,13b-dihydro-1H-dibenz [c, f] imidazo [1,5-a] azepepine hydrochloride; 158-162 ° C (dec.) (alcohol / ether mixture). The material contains 0.25 moles of water.

(e) 3-Pietylamino-9,13b-dihydro-1H-dibenz [c, f] imidazo [1,5-a] azepine hydrochloride; m.p. 234 'C (decomposed from methanol / ether);

(f) 3-ethylamino-9,13b-dihydro-1H-dibenz [c, f] imidazo [1,5-a] azepine hydrochloride; 275-280 ° C;

(g) 3-Allylamino-1,13b-dihydro-1H-dibenz [c, f] imidazo [1,5-a] azepine hydrochloride; m.p. 202-205 ° C (from acetonitrile / ethyl acetate).

Example 5 3-Dimethylamino-7-chloro-9,13b-dihydro-1 H -dibenz [c, f] imidazo- [1,5-a] azepine hydrochloride

To a solution of 6.7 g (0.026 mol) of 6-aminomethyl-2-chloro-6,11-dihydro-5 H -dibenz [b, ejazepine and 5.76 (0.057 mol) triethylamine in 70 ml of chloroform was added 4.21 g ( Dichloromethylene dimethylammonium chloride (0.026 mol) was added. Slightly exothermic reaction occurs. The reaction mixture was then stirred for an additional hour

The mixture is refluxed for 5 hours, cooled and extracted with 2N hydrochloric acid and 2N sodium hydroxide solution. The organic layer was washed with water, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue is then chromatographed on silica gel. The impurities are first separated with acetone and methanol, and then the desired product is cloned with 65: 35: 1 chloroform: methanol: concentrated ammonia. Evaporation of chloroform, methanol and concentrated ammonia gave 4.5 g of an oil. The crude product was dissolved in ether and, after filtration of the insoluble particles, converted to the hydrochloride with methanolic hydrochloric acid.

Yield: 3.7 g (40%). 195-197 ° C (from acetonitrile / ethyl acetate). The product contains 0.5 moles of water.

Example 6 3-Methylamino-6-chloro-9,13b-dihydro-dibenz [b, f] imidazo [1,5-d] - [1,4] oxazepine hydrochloride (T) 9.2 g (0.035 mol) A mixture of 11-aminomethyl-8-chloro-10,11-dihydrodibenz [b, f] [1,4] oxazepine and 2.58 g (0.035 mol) of methyl isocyanate was stirred at room temperature for 2 hours, then allowed to stand overnight. Concentration of the reaction mixture gave 11.7 g of crystalline material. 126-132 ° C.

(II) 10 g of the thiourea derivative prepared above are dissolved in a solution of 6.38 g (0.045 mol) of methyl iodide in 80 ml of methanol and the reaction mixture is refluxed for two hours. N- (8-chloro-10,11-dihydro-dibenz [b, f] - [1,4] oxazepin-11-ylmethyl) -S-methylisothiourea hydroiodide is obtained (m.p. 212-215 ° C), suction and dry.

(III) To prepare the base, 9.7 g of the hydroiodide prepared in (II) is suspended in water and 2N sodium hydroxide solution and ether are added and the reaction mixture is stirred until two clear phases are obtained. The organic layer was separated, dried over anhydrous sodium sulfate and concentrated in vacuo. The resulting product (7.1 g, 0.02 mol base) was dissolved in xylene (60 ml) and refluxed for 11 hours. While cooling the reaction solution, the crystalline solid (5.6 g) was filtered off with suction, dissolved in methanol and converted to the hydrochloride with ethereal hydrochloric acid. For further purification, the salt is treated with dilute sodium acetate solution. The aqueous solution was extracted twice with ether, basified with sodium hydroxide solution and then extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The residual base was converted to the hydrochloride salt. Yield: 4.1 g (61%), m.p. 297-300 ° C (from methanol / ether).

Analogous to (I) and (II), starting from 11-aminomethyl-10,11-dihydro-dibenz [b, f] [1,4] oxazepine, N- (10,11-dihydro-dibenz [b, f] [ 1,4-oxazepin-11-ylmethyl) -S-methylisothiourea hydroiodide is obtained. The base prepared from the compound was heated in toluene for three hours; methyl mercaptan is cleaved to give 3-methylamino-9,13b-dihydro-dibenz [b, f] 6-imidazo [1,5-d] - [1,4] oxisepine. The hydrochloride has a melting point of 328-330 ° C.

Example 7 3-Methylamino-7-chloro-9,13b-dihydro-dibenz [b, f] imidazo [1,5-d] - [1,4] oxazepine hydrochloride (T) N- (7-Chloro) 10,11-Dihydro-dibenz [b, f] [1,4] oxazepin-11-yl) -X-methylurea g (0.042 mol) 11-aminomethyl-7-chloro-10,11-dihydro-dibenz [ To a solution of b, f] [1,4] oxazepine in 60 mL of toluene was added dropwise a solution of 2.68 g (0.045 mol) of methyl isocyanate in 40 mL of toluene. After a reaction time of 2 hours, the precipitated crystals are filtered off with suction and dried.

Yield: 10.8 g (80%); 146-

149 ° C.

(TI) 10.8 g (0.034 mol) of the carbartylide derivative prepared in (I) are suspended in 200 ml of toluene and reacted with 10.8 ml of phosphorus oxychloride. The reaction mixture was refluxed for 30 minutes. After evaporation of the solvent, the residue is partitioned between cold dilute sodium hydroxide solution and chloroform. The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. Yield: 6.2 g (60.9%); mp 163-165 ° C (from acetonitrile). The hydrochloride salt prepared in the usual manner has a melting point of 298-302 ° C (from a mixture of methanol and ethyl acetate).

Starting from 6-aminomethyl-6,11-dihydro-5H-dibenz [b, e] azepine, reacting with isopropyl isocyanate affords the urea (m.p. 190-192 ° C), which in analogy to process b) is 3-isopropylamino. 9,13b-dihydro-1H-dibenz [c, f] imidazo [1,5-a] azepine.

Melting point: 241-243 ° C (dec.).

Example 8 (-) - 3-Amino-9,13b-dihydro-1H-dibenz [c, f] imidazo [1,5-a] azepine hydrochloride or (+) - 3-amino-9,13b- dihydro-1H-dibenz- [e, f] imidazo [1,5-a] aze- * pine hydrochloride

36.5 g (0.146 mol) of racemic 3-amino-9,13b-dihydrodibenz [c, f] imidazo [1,5-a] azepine base and 55.1 g (0.164 mol) of dibenzoyl-L (+) - tartaric acid was dissolved in 1 liter of methanol with heating.

Upon cooling, a precipitate forms which is filtered off after a longer period of standing. The precipitated crystals are crystallized from methanol until the melting point and rotation are constant. Mp:

150-152 ° C; [α] D = -200, (c = I, methanol).

The base prepared in the usual manner is dissolved in methanol and converted to the hydrochloride with ethereal hydrochloric acid.

266-269 ° C; [.Alpha.] D @ 20 = -285 DEG (c = 1, alcohol).

In an analogous manner to the dibenzoyl-D (-) - tartaric acid, the (+) enantiomer can be prepared.

M.p. 266-269 ° C.

[.alpha.] D @ ²⁰ = + 285 DEG (c = 1, alcohol).

Claims (2)

Patent claims 1. A process for the preparation of compounds of formula I in the form of their racemates and enantiomers or mixtures of enantiomers, as the free base, as ⁷ acid addition salts, wherein: R ₂ , R ₂ , R ₃ and R ₄ are each independently hydrogen or halogen, C 1-6 alkyl or alkoxy; R ₅ and R ₆ each independently represent hydrogen, C 1-6 alkyl or C 3-6 alkenyl, cut} ⁷ R ₅ and R ₆ together with the nitrogen atom form a pyrrolidino, piperidino or morpholino group, and X cuts oxygen or sulfur} represents ⁷ methylene groups, characterized in that a) a II, a compound of formula - Y in this formula is halogen, preferably chlorine, or an alkoxy or alkylthio group, R, R _2, R _3, R ₄ and Y are as defined above - with an amine of TII formula - R _s and R _{6) in} the presence or solvent of a solvent as defined above; obsession b) for the preparation of compounds of formula I wherein R ₅ and R _{6 are} hydrogen and the other substituents are as defined in the foregoing, a compound of formula IV - wherein R _x , R ₂ , R ₃ , R ₄ and X a by reacting with a halogen cyanide and an intermediate of formula IVa in which R _{1 is as defined above.} R ₂ , R ₃ , R ₄ and X are as defined above - intramolecularly cyclizing; obsession c) a VIII to a compound of formula - in which R ₄ -R _fi as defined above and Q is O, S or = NR ₇ and wherein R ₇ is hydrogen or optionally 5 substituted C 1-8 alkyl group - is reacted with an acid halide, preferably phosphoryl trichloride, and the sulfur Q and R _e hydrogen are alkylated to give the corresponding isothiocarbanide IX - R 1, R ₂ , R ₃ , R ₄ , R ₆ and X are as defined above, R is an optionally substituted C1-8 alkyl cut -iners solvent} ⁷ was subjected to cyclization by heating in the melt; or d) reacting a diamine of formula IV, as defined above, with an N, N-disubstituted dichloromethylenimine imine salt of formula X, wherein R ₅ and R _{6 are} as defined above, and optionally a resulting racemate to its enantiomeric 20 separating and / or converting a resulting free base into an acid addition salt, converting the resulting acid addition salt into a free base. 2. A process for the preparation of a compound of formula I in the form of its racemate, enantiomer or thiomers of enan25 as the free base or acid addition salt thereof, in which R _{1 is;} R _2, R _3, R _4, R _5, R _e and X are as defined in the preamble of claim 1 having the meaning of - containing pharmaceutical preparation wherein the active ingredient prepared in any method of 1 to 30 claim conventional pharmaceutical carrier, diluent , fillers and / or other excipients, in the form of a pharmaceutical composition.